title: Design and application of a rigid quinazolone scaffold based on two-face Bim α-helix mimicking.
abstract: Based on our previous discovery of an anthraquinone scaffold mimicking two faces of Bim α-helix, we derived a quinazolone scaffold through structure simplification and optimization. It was inferred that a rigid bicyclic ring was necessary and efficient to maintain the two-faced binding mode. A novel dual inhibitor 6c [6,7,8-trihydroxy-3-(2-hydroxy-5-methylbenzyl)-2-phenylquinazolin-4(3H)-one] was obtained based on this scaffold. 6c exhibited dual binding activity with K(i) values of 0.123 μM for Mcl-1 and 0.179 μM for Bcl-2.
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian 116012, People's Republic of China. Electronic address: zczhang@dlut.edu.cn.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Liang
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Li
authors.forename: Ting
authors.initials: T
authors.lastname: Song
authors.forename: Qingbin
authors.initials: Q
authors.lastname: Chen
authors.forename: Hongkun
authors.initials: H
authors.lastname: Sheng
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines
keywords: Bcl-2; JQFLKAJQKGNCSW-UHFFFAOYSA-N; Mcl-1; Quinazolone; RNUPWQDKOJAKGW-UHFFFAOYSA-N; SYEGIOUDEHFYQT-UHFFFAOYSA-N; Two-faced; UGGKGLCTXKBKQS-UHFFFAOYSA-N; α-Helix